Cited by 615Tryptophan and brain disordersNeuroinflammation and Neurodegeneration MechanismsTreatment of Major Depression

The DOI matches its Crossref record; 95 of the 97 references it cites were found in a registry or an index.

Markers of central inflammation in major depressive disorder: A systematic review and meta-analysis of studies examining cerebrospinal fluid, positron emission tomography and post-mortem brain tissue

Open access

Enache, Daniela, Pariante, Carmine M., Mondelli, Valeria·2019·Brain, Behavior, and Immunity

DOI 10.1016/j.bbi.2019.06.015

Open this paper in CoChat — free account

Abstract

BACKGROUND Increased peripheral inflammation has been consistently reported in patients with major depressive disorder (MDD). However, only few studies have explored markers of central (brain) inflammation in patients with MDD. The aim of this study is to systematically review in vivo and post-mortem markers of central inflammation, including studies examining cerebrospinal fluid (CSF), positron emission tomography, and post-mortem brain tissues in subjects suffering with MDD compared with controls. METHODS PubMed and Medline databases were searched up to December 2018. We included studies measuring cerebrospinal fluid (CSF) cytokines and chemokines, positron emission tomography (PET) studies; and post-mortem studies measuring cytokines, chemokines and cell-specific markers of microglia and astrocytes, all in MDD. A meta-analysis was performed only for CSF and PET studies, as studies on post-mortem markers of inflammation had different cell-specific markers and analysed different brain regions. RESULTS A total of 69 studies met the inclusion criteria. CSF levels of IL-6 and TNF-α were higher in patients with MDD compared with controls (standardised mean difference SMD 0.37, 95%CI: 0.17-0.57 and SMD 0.58, 95%CI 0.26-0.90, respectively). CSF levels of IL-6 were increased in suicide attempters regardless of their psychiatric diagnosis. Translocator protein, a PET marker of central inflammation, was elevated in the anterior cingulate cortex and temporal cortex of patients with MDD compared with controls (SMD 0.78, 95%CI: 0.41-1.16 and SMD 0.52, 95%CI: 0.19-0.85 respectively). Abnormalities in CSF and PET inflammatory markers were not correlated with those in peripheral blood. In post-mortem studies, two studies found increased markers of microglia in MDD brains, while four studies found no MDD related changes. Of the studies investigating expression of cell-specific marker for astrocytes, thirteen studies reported a decreased expression of astrocytes specific markers, two studies reported increased expression of astrocytes specific markers, and eleven studies did not detect any difference. Four out of six studies reported decreased markers of oligodendrocytes in the prefrontal cortex. Post-mortem brain levels of tumor necrosis alpha (TNF-α) were also found increased in MDD. CONCLUSIONS Our review suggests the presence of an increase in IL-6 and TNF-alpha levels in CSF and brain parenchyma, in the context of a possible increased microglia activity and reduction of astrocytes and oligodendrocytes markers in MDD. The reduced number of astrocytes may lead to compromised integrity of blood brain barrier with increased monocyte recruitment and infiltration, which is partly supported by post-mortem studies and by PET studies showing an increased TSPO expression in MDD.

Integrity signals

Registry

Crossref · 10.1016/j.bbi.2019.06.015

Cites

95 of 95 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

The text we found for this paper looks like another document, so its claims and self-check weren’t run. The registry and citation checks still apply.

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The text we found for this paper looks like another document, so the self-check wasn’t run.

Estimating the mean and variance from the median, range, and the size of a sample
Hozo, S. P., Djulbegovic, B., & Hozo, I. (2005) · BMC Medical Research Methodology · doi:10.1186/1471-2288-5-13 · Cited by 9,062
The role of inflammation in depression: from evolutionary imperative to modern treatment target
Miller, A. H., & Raison, C. L. (2016) · Nature Reviews Immunology · doi:10.1038/nri.2015.5 · Cited by 3,942
Physiology of Astroglia
Verkhratsky, A., & Nedergaard, M. (2018) · Physiological Reviews · doi:10.1152/physrev.00042.2016 · Cited by 1,678 · cited 1×
“Astrocytes play a key role in maintaining the neurotransmitters homeostasis (glutamate and GABA), water transport homeostasis, ion homeostasis, metabolic support, synaptogenesis and synaptic plasticity, maintaining the integrity of the blood brain barrier (Verkhratsky and Nedergaard, 2018).”
Background
Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications
Felger, J. C., & Lotrich, F. E. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.04.060 · Cited by 1,180 · cited 1×
“Cytokines administration has been shown to induce activation of the hypothalamic–pituitary–adrenal (HPA) axis and peripheral glucocorticoid secretion (Felger and Lotrich, 2013).”
Background
Role of Translocator Protein Density, a Marker of Neuroinflammation, in the Brain During Major Depressive Episodes
Setiawan, E., Wilson, A. A., Mizrahi, R., Rusjan, P. M., Miler, L., Rajkowska, G., Suridjan, I., Kennedy, J. L., Rekkas, P. V., Houle, S., et al. (2015) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2014.2427 · Cited by 939 · cited 2×
“Seven studies found no correlation between markers of central inflammation (CSF cytokines or PET TSPO) and peripheral inflammation (Bay-Richter et al., 2015; Hannestad et al., 2013; Holmes et al., 2018; Isung et al., 2012; Lindqvist et al., 2009; Sasayama et al., 2013; Setiawan et al., 2015).”
Background
Evaluation of the endorsement of the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement on the quality of published systematic review and meta-analyses
Panic, N., Leoncini, E., de Belvis, G., Ricciardi, W., & Boccia, S. (2013) · PLoS ONE · doi:10.1371/journal.pone.0083138 · Cited by 883 · cited 1×
“This study followed the PRISMA guidelines for conducting and reporting systematic reviews (Panic et al., 2013).”
Method
Immunological aspects in the neurobiology of suicide: Elevated microglial density in schizophrenia and depression is associated with suicide
Steiner, J., Bielau, H., Brisch, R., Danos, P., Ullrich, O., Mawrin, C., Bernstein, H.-G., & Bogerts, B. (2008) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2006.10.013 · Cited by 791
Inflammation-associated depression: From serotonin to kynurenine
Dantzer, R., O’Connor, J. C., Lawson, M. A., & Kelley, K. W. (2011) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2010.09.012 · Cited by 726 · cited 3×
“23 The concomitant activation of microglia and reduced function of astrocytes could also have downstream effects on the kynurenine pathway (Dantzer et al., 2011).”
BackgroundInfluential
Oligodendroglial density in the prefrontal cortex in schizophrenia and mood disorders: a study from the Stanley Neuropathology Consortium
Uranova, N. A., Vostrikov, V. M., Orlovskaya, D. D., & Rachmanova, V. I. (2004) · Schizophrenia Research · doi:10.1016/s0920-9964(03)00181-6 · Cited by 659
Astrocyte Pathology in Major Depressive Disorder: Insights from Human Postmortem Brain Tissue
Rajkowska, G., & Stockmeier, C. (2013) · Current Drug Targets · doi:10.2174/13894501113149990156 · Cited by 603 · cited 14×
“CSF levels of IL-6 and TNF-α were higher in patients with MDD compared with controls (standardised mean difference SMD 0.37, 95%CI: 0.17-0.57 and SMD 0.58, 95%CI 0.26-0.90, respectively).”
BackgroundInfluential

Show all 97 references

Sorted by citations

COVID-19 pandemic and mental health consequences: Systematic review of the current evidence
Vindegaard, N., & Benros, M. E. (2020) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2020.05.048 · Cited by 3,221
The Bidirectional Relationship of Depression and Inflammation: Double Trouble
Beurel, E., Toups, M., & Nemeroff, C. B. (2020) · Neuron · doi:10.1016/j.neuron.2020.06.002 · Cited by 2,136
“Furthermore, a recent meta-analysis suggests increased microglial activity is associated with increased IL-6, IL-8, and TNF levels in CSF and brain parenchyma of MDD patients (Wang and Miller, 2018) and reduced astrocytes and oligodendrocytes numbers in MDD patients (Enache et al., 2019).”
Background
Major depressive disorder
Marx, W., Penninx, B. W. J. H., Solmi, M., Furukawa, T. A., Firth, J., Carvalho, A. F., & Berk, M. (2023) · Nature Reviews Disease Primers · doi:10.1038/s41572-023-00454-1 · Cited by 910
Comorbid depression in medical diseases
Gold, S. M., Köhler‐Forsberg, O., Moss-Morris, R. E., Mehnert-Theuerkauf, A., Miranda, J. J., Bullinger, M., Steptoe, A., Whooley, M. A., & Otte, C. (2020) · Nature Reviews Disease Primers · doi:10.1038/s41572-020-0200-2 · Cited by 583
Persistent psychopathology and neurocognitive impairment in COVID-19 survivors: effect of inflammatory biomarkers at three-month follow-up
Mazza, M. G., Palladini, M., De Lorenzo, R., Magnaghi, C., Poletti, S., Furlan, R., Ciceri, F., Rovere-Querini, P., & Benedetti, F. (2021) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2021.02.021 · Cited by 513
“Depressed patients are characterized by higher levels of cytokines when compared to healthy controls with consistent results in literature when considering IL-1β, IL6, IL-10, CCL2, TNF-α, and transforming growth factor-β (TGF-β) (Enache et al., 2019; Eyre et al., 2016; Howren et al., 2009; Kohler et al., 2017; Poletti…”
Depression Heterogeneity and Its Biological Underpinnings: Toward Immunometabolic Depression
Milaneschi, Y., Lamers, F., Berk, M., & Penninx, B. W. J. H. (2020) · Biological Psychiatry · doi:10.1016/j.biopsych.2020.01.014 · Cited by 451
Immune targets for therapeutic development in depression: towards precision medicine
Drevets, W. C., Wittenberg, G. M., Bullmore, E. T., & Manji, H. K. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00368-1 · Cited by 348
Major Depressive Disorder: Advances in Neuroscience Research and Translational Applications
Li, Z., Ruan, M., Chen, J., & Fang, Y. (2021) · Neuroscience Bulletin · doi:10.1007/s12264-021-00638-3 · Cited by 372
Microglia in depression: current perspectives
Jia, X., Gao, Z., & Hu, H. (2020) · Science China Life Sciences · doi:10.1007/s11427-020-1815-6 · Cited by 288
“In meta-analysis of depression studies, patients with depression showed consistently upregulated levels of pro-inflammatory cytokines such as TNF-α and IL-6 (Dowlati et al., 2010; Enache et al., 2019).”
Background
Neuroinflammation in psychiatric disorders: PET imaging and promising new targets
Meyer, J. H., Červenka, S., Kim, M.-J., Kreisl, W. C., Henter, I. D., & Innis, R. B. (2020) · The Lancet Psychiatry · doi:10.1016/s2215-0366(20)30255-8 · Cited by 287
Oligodendrocyte lineage cells and depression
Zhou, B., Zhu, Z., Ransom, B. R., & Tong, X. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-00930-0 · Cited by 245
Gut microbiota–brain axis in depression: the role of neuroinflammation
Carlessi, A. S., Borba, L. A., Zugno, A. I., Quevedo, J., & Réus, G. Z. (2021) · European Journal of Neuroscience · doi:10.1111/ejn.14631 · Cited by 243
Augmentation therapy with minocycline in treatment-resistant depression patients with low-grade peripheral inflammation: results from a double-blind randomised clinical trial
Nettis, M. A., Lombardo, G., Hastings, C., Zajkowska, Z., Mariani, N., Nikkheslat, N., Worrell, C., Enache, D., McLaughlin, A., Kose, M., et al. (2021) · Neuropsychopharmacology · doi:10.1038/s41386-020-00948-6 · Cited by 235
Self-citation
The intestinal barrier in disorders of the central nervous system
Pellegrini, C., Fornai, M., D'Antongiovanni, V., Antonioli, L., Bernardini, N., & Derkinderen, P. (2023) · The Lancet Gastroenterology & Hepatology · doi:10.1016/s2468-1253(22)00241-2 · Cited by 239
Omega-3 polyunsaturated fatty acids protect against inflammation through production of LOX and CYP450 lipid mediators: relevance for major depression and for human hippocampal neurogenesis
Borsini, A., Nicolaou, A., Camacho‐Muñoz, D., Kendall, A. C., Benedetto, M. G. D., Giacobbe, J., Su, K., & Pariante, C. M. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01160-8 · Cited by 235
Self-citation
Psychiatric face of COVID-19
Steardo, L., Steardo, L., & Verkhratsky, A. (2020) · Translational Psychiatry · doi:10.1038/s41398-020-00949-5 · Cited by 227
Post-COVID-19 Depressive Symptoms: Epidemiology, Pathophysiology, and Pharmacological Treatment
Mazza, M. G., Palladini, M., Poletti, S., & Benedetti, F. (2022) · CNS Drugs · doi:10.1007/s40263-022-00931-3 · Cited by 248
“Accordingly, increased microglial activation in association with high levels of IL-6 and TNF-α have been observed in MDD episodes [82], whereas microglia activation has been implicated in both acute and chronic neurological complications of COVID-19 [83], and increased microglial activation has been demonstrated in po…”
Background
Microglial ERK-NRBP1-CREB-BDNF Signaling in Sustained Antidepressant Actions of (R)-Ketamine
Yao, W., Cao, Q., Luo, S., He, L., Yang, C., Chen, J., Qi, Q., Hashimoto, K., & Zhang, J.-C. (2022) · Molecular Psychiatry · doi:10.1038/s41380-021-01377-7 · Cited by 216
“A recent meta-analysis using positron emission tomography data showed increased expression of microglia in the brain of patients with depression [71].”
Method
PI3K/AKT signaling pathway: Molecular mechanisms and therapeutic potential in depression
Guo, N., Wang, X., Xu, M., Bai, J., Yu, H., & Zhang, L. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107300 · Cited by 237
Biological factors influencing depression in later life: role of aging processes and treatment implications
Szymkowicz, S. M., Gerlach, A., Homiack, D., & Taylor, W. D. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02464-9 · Cited by 234
“Studies of individuals with depression and suicide attempts report increased microglial activation in the anterior cingulate cortex (ACC), a key hub of both the ASN and CCN, in individuals with depression and suicide attempts [131, 132].”
Background
Climate change, environment pollution, COVID-19 pandemic and mental health
Marazziti, D., Cianconi, P., Mucci, F., Crowther, L. F., Chiarantini, I., & Vecchia, A. D. (2021) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2021.145182 · Cited by 204
“Depression was associated with elevated IL-6 concentrations in both plasma and brain (Lindqvist et al., 2009; Sasayama et al., 2013; Kern et al., 2014; Enache et al., 2019; Boufidou et al., 2009; Hodes et al., 2016).”
Psycho-Neuroendocrine-Immune Interactions in COVID-19: Potential Impacts on Mental Health
Raony, Í., de Figueiredo, C. S., Pandolfo, P., Giestal-de-Araujo, E., Oliveira-Silva Bomfim, P., & Savino, W. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01170 · Cited by 185
How inflammation affects the brain in depression: a review of functional and structural MRI studies
Han, K.-M., & Ham, B.-J. (2021) · Journal of Clinical Neurology · doi:10.3988/jcn.2021.17.4.503 · Cited by 187
Depression, dementia and immune dysregulation
Hayley, S., Hakim, A. M., & Albert, P. R. (2021) · Brain · doi:10.1093/brain/awaa405 · Cited by 186
“, 2017), post-mortem studies in human brain have detected inflammatory cytokines and microglial activation markers in depression and suicide (Enache et al., 2019).”
Background
The role of exercise in the treatment of depression: biological underpinnings and clinical outcomes
Ross, R. E., VanDerwerker, C. J., Saladin, M. E., & Gregory, C. M. (2023) · Molecular Psychiatry · doi:10.1038/s41380-022-01819-w · Cited by 176
A specific inflammatory profile underlying suicide risk? Systematic review of the main literature findings
Serafini, G., Parisi, V. M., Aguglia, A., Amerio, A., Sampogna, G., Fiorillo, A., Pompili, M., & Amore, M. (2020) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph17072393 · Cited by 172
“[52] supported the existence of abnormally increased IL-6 and TNF-α concentrations in CSF and brain parenchyma, together with an increased microglia activity and abnormally reduced astrocytes/oligodendrocytes markers levels in MDD.”
Background
Past, Present and (Foreseeable) Future of Biological Anti-TNF Alpha Therapy
Leone, G. M., Mangano, K., Petralia, M. C., Nicoletti, F., & Fagone, P. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12041630 · Cited by 177
Depression in Alzheimer’s Disease: Epidemiology, Mechanisms, and Treatment
Huang, Y.-Y., Gan, Y.-H., Yang, L., Cheng, W., & Yu, J.-T. (2024) · Biological Psychiatry · doi:10.1016/j.biopsych.2023.10.008 · Cited by 164
Inflammatory mediators in major depression and bipolar disorder
Poletti, S., Mazza, M. G., & Benedetti, F. (2024) · Translational Psychiatry · doi:10.1038/s41398-024-02921-z · Cited by 195
The Ketogenic Diet for Refractory Mental Illness: A Retrospective Analysis of 31 Inpatients
Danan, A., Westman, E. C., Saslow, L. R., & Ede, G. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.951376 · Cited by 165
Stress-induced NLRP3 inflammasome activation negatively regulates fear memory in mice
Dong, Y., Li, S., Lu, Y., Li, X., Liao, Y., Peng, Z., Li, Y., Hou, L., Yuan, Z., & Cheng, J. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01842-0 · Cited by 148
The SARS-CoV-2 and mental health: From biological mechanisms to social consequences
Szcześniak, D. M., Gładka, A., Misiak, B., Cyran, A., & Rymaszewska, J. (2020) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2020.110046 · Cited by 157
Neuroinflammation—A Crucial Factor in the Pathophysiology of Depression—A Comprehensive Review
Sălcudean, A., Bodo, C.-R., Popovici, R. A., Lica, M. M., Păcurar, M., Crăciun, R.-E., Crișan, A., ENĂTESCU, V. R., Marinescu, I. P., Cîmpian, D. M., et al. (2025) · Biomolecules · doi:10.3390/biom15040502 · Cited by 179
Gut-derived systemic inflammation as a driver of depression in chronic liver disease
Kronsten, V. T., Tranah, T. H., Pariante, C. M., & Shawcross, D. L. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2021.11.008 · Cited by 137
Self-citation
“Inflamed” depression: A review of the interactions between depression and inflammation and current anti-inflammatory strategies for depression
Yin, Y., Ju, T., Zeng, D., Duan, F., Zhu, Y., Liu, J., Li, Y., & Lu, W. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107322 · Cited by 159
Novel neuroimmunologic therapeutics in depression: A clinical perspective on what we know so far
Roman, M., & Irwin, M. R. (2020) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2019.09.016 · Cited by 132
“This increase of CSF levels of TNFα and Il-6 in depressed individuals was further corroborated by a systematic review and meta-analysis of 69 studies, which also demonstrated an increase of these two inflammatory markers in the brain parenchyma in depression (Enache et al., 2019).”
Result
The complex interplay between depression and multimorbidity in late life: risks and pathways
Triolo, F., Harber-Aschan, L., Murri, M. B., Calderón‐Larrañaga, A., Vetrano, D. L., Sjöberg, L., Marengoni, A., & Dekhtyar, S. (2020) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2020.111383 · Cited by 136
“…been linked with subsequent depression and multimorbidity, with evidence pointing to the relevance of critical windows of stress in childhood, as well as over prolonged life periods (Brodbeck et al., 2018; England-Mason et al., 2018; Henchoz et al., 2019; Sinnott et al., 2015; Triolo et al., 2020).”
Background
Peripheral and central kynurenine pathway abnormalities in major depression
Paul, E. R., Schwieler, L., Erhardt, S., Boda, S., Trepci, A., Kämpe, R., Asratian, A., Holm, L., Yngve, A., Dantzer, R., et al. (2022) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2022.01.002 · Cited by 134
“Increased circulating pro-inflammatory cytokines are among the most reliably observed findings in the biologicalpsychiatry of MDD (Dowlati et al., 2010; Enache et al., 2019; Köhler et al., 2017).”
Toll-Like Receptor Signaling in Depression
Figueroa‐Hall, L. K., Paulus, M. P., & Savitz, J. B. (2020) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2020.104843 · Cited by 122
“A number of systematic reviews and meta-analyses have shown that interleukin 6 (IL-6), IL-1β, C-reactive protein (CRP), tumor necrosis factor (TNF), and IL-1 receptor antagonist (IL-1Ra) are positively associated with MDD (Dowlati et al., 2010; Enache et al., 2019; Goldsmith et al., 2016; Haapakoski et al., 2015).”
Background
Aiding and Abetting Anhedonia: Impact of Inflammation on the Brain and Pharmacological Implications
Lucido, M. J., Bekhbat, M., Goldsmith, D. R., Treadway, M. T., Haroon, E., Felger, J. C., & Miller, A. H. (2021) · Pharmacological Reviews · doi:10.1124/pharmrev.120.000043 · Cited by 133
“microglia, the immune cells of the brain (Pandey et al., 2014, 2017; Torres-Platas et al., 2014a,b; Enache et al., 2019).”
Background
The immunology of stress and the impact of inflammation on the brain and behaviour
Ravi, M., Miller, A. H., & Michopoulos, V. (2021) · BJPsych Advances · doi:10.1192/bja.2020.82 · Cited by 130
“Increased microglia activation, the central mediators of the immune system, as assessed by PET neuroimaging, and greater expression of TNF and TLR4 in post-mortem brain tissue have also been described in individuals with depression (27).”
Blood–Brain Barrier Dysfunction in the Pathogenesis of Major Depressive Disorder
Wu, S., Yin, Y., & Du, L. (2021) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-021-01153-9 · Cited by 127
Blood brain barrier and inflammation in depression
Medina-Rodriguez, E. M., & Beurel, E. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105926 · Cited by 123
Depression: Biological markers and treatment
Erjavec, G. N., Šagud, M., Perković, M. N., Štrac, D. Š., Konjevod, M., Tudor, L., Uzun, S., & Pivac, N. (2020) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2020.110139 · Cited by 127
Psychological Symptoms in COVID-19 Patients: Insights into Pathophysiology and Risk Factors of Long COVID-19
Thye, A. Y.-K., Law, J. W., Tan, L. T., Pusparajah, P., Ser, H., Thurairajasingam, S., Letchumanan, V., & Lee, L. (2022) · Biology · doi:10.3390/biology11010061 · Cited by 122
Dihydrolipoic acid protects against lipopolysaccharide-induced behavioral deficits and neuroinflammation via regulation of Nrf2/HO-1/NLRP3 signaling in rat
Bian, H., Wang, G., Huang, J., Liang, L., Zheng, Y., Wei, Y., Wang, H., Xiao, L., & Wang, H. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01836-y · Cited by 112
The molecular pathophysiology of depression and the new therapeutics
Tian, H., Hu, Z., Xu, J., & Wang, C. (2022) · MedComm · doi:10.1002/mco2.156 · Cited by 122
Immuno-metabolic depression: from concept to implementation
Penninx, B. W. J. H., Lamers, F., Jansen, R., Berk, M., Khandaker, G. M., Picker, L. D., & Milaneschi, Y. (2024) · The Lancet Regional Health - Europe · doi:10.1016/j.lanepe.2024.101166 · Cited by 131
Sick for science: experimental endotoxemia as a translational tool to develop and test new therapies for inflammation-associated depression
Lasselin, J., Lekander, M., Benson, S., Schedlowski, M., & Engler, H. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-00869-2 · Cited by 121
“This TSPO binding pattern was similar to those in patients with MDD, for which a meta-analysis reported increased TSPO expression in ACC, frontal lobe, prefrontal and temporal cortices, insula, and hippocampus when compared to healthy controls [71].”
Result
Possible antidepressant mechanisms of omega-3 polyunsaturated fatty acids acting on the central nervous system
Zhou, L., Xiong, J., Chai, Y.-Q., Huang, L., Tang, Z.-Y., Zhang, X., Liu, B., & Zhang, J.-T. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.933704 · Cited by 119
Choroid plexus enlargement is associated with neuroinflammation and reduction of blood brain barrier permeability in depression
Althubaity, N., Schubert, J. J., Martins, D., Yousaf, T., Nettis, M. A., Mondelli, V., Pariante, C. M., Harrison, N. A., Bullmore, E. T., Dima, D., et al. (2021) · NeuroImage Clinical · doi:10.1016/j.nicl.2021.102926 · Cited by 116
Self-citation
Neuroimmune Mechanisms Underlying Neuropathic Pain: The Potential Role of TNF-α-Necroptosis Pathway
Duan, Y.-W., Chen, S., Li, Q., & Zang, Y. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23137191 · Cited by 117
Inflammation as a treatment target in mood disorders: review
Jones, B. D. M., Daskalakis, Z. J., Carvalho, A. F., Strawbridge, R., Young, A. H., Mulsant, B. H., & Husain, M. I. (2020) · BJPsych Open · doi:10.1192/bjo.2020.43 · Cited by 106
Neuroinflammation, Pain and Depression: An Overview of the Main Findings
Campos, A. C. P., Antunes, G. F., Matsumoto, M., Pagano, R. L., & Martinez, R. C. R. (2020) · Frontiers in Psychology · doi:10.3389/fpsyg.2020.01825 · Cited by 107
“Neuroimaging and postmortem studies have shown an increase in mitochondrial translocator protein (tryptophan-rich sensory proteins -TSPO) in subjects with major depressive disorder (Enache et al., 2019).”
Background
Ketamine’s effect on inflammation and kynurenine pathway in depression: A systematic review
Kopra, E. I., Mondelli, V., Pariante, C. M., & Nikkheslat, N. (2021) · Journal of Psychopharmacology · doi:10.1177/02698811211026426 · Cited by 106
“Increased inflammatory markers, specifically C-reactive protein (CRP), interleukin (IL)-1, IL-6, and tumornecrosis factor alpha (TNF-α), have been observed in the blood and cerebrospinal fluid (CSF) as well as in postmortem brain samples of MDD and BD patients (Enache et al., 2019; Osimo et al., 2020; Raison et al., 2…”
BackgroundSelf-citation
Targeting neuroinflammation by polyphenols: A promising therapeutic approach against inflammation-associated depression
Tayab, M. A., Islam, M. N., Chowdhury, K. A. A., & Tasnim, F. M. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.112668 · Cited by 100
Cerebrospinal Fluid Biomarkers in Patients With Unipolar Depression Compared With Healthy Control Individuals
Mousten, I. V., Sørensen, N. V., Christensen, R. H. B., & Benros, M. E. (2022) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2022.0645 · Cited by 99
Sex differences in the blood–brain barrier: Implications for mental health
Dion‐Albert, L., Binder, L. B., Daigle, B., Hong-Minh, A., Lebel, M., & Ménard, C. (2022) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2022.100989 · Cited by 93
“Changes in central and peripheral inflammatory mediators have been observed in MDD (Enache et al., 2019; Schiepers et al., 2005), BD (O’Brien et al.”
Background
Systems biology dissection of PTSD and MDD across brain regions, cell types, and blood
Daskalakis, N. P., Iatrou, A., Chatzinakos, C., Jajoo, A., Snijders, C., Wylie, D., DiPietro, C. P., Tsatsani, I., Chen, C.-Y., Pernia, C. D., et al. (2024) · Science · doi:10.1126/science.adh3707 · Cited by 109
Single-cell mass cytometry of microglia in major depressive disorder reveals a non-inflammatory phenotype with increased homeostatic marker expression
Böttcher, C., Fernández‐Zapata, C., Snijders, G. J. L., Schlickeiser, S., Sneeboer, M. A. M., Kunkel, D., de Witte, L. D., & Priller, J. (2020) · Translational Psychiatry · doi:10.1038/s41398-020-00992-2 · Cited by 92
Ketogenic diet as a metabolic treatment for mental illness
Norwitz, N. G., Sethi, S., & Palmer, C. (2020) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0000000000000564 · Cited by 99
Increased serum peripheral C-reactive protein is associated with reduced brain barriers permeability of TSPO radioligands in healthy volunteers and depressed patients: implications for inflammation and depression
Turkheimer, F., Althubaity, N., Schubert, J. J., Nettis, M. A., Cousins, O., Dima, D., Mondelli, V., Bullmore, E. T., Pariante, C. M., & Veronese, M. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.10.025 · Cited by 89
Self-citation
Noteworthy perspectives on microglia in neuropsychiatric disorders
Zhu, H., Guan, A., Liu, J., Li, P., Zhang, Z., & Wang, S. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02901-y · Cited by 91
“…in post-mortem brains of MDD individuals, may cause disruption of BBB integrity and subsequently infiltration of monocytes into the CNS, which can also display increased TSPO in PET [236]; on the other hand, microglia activation may not persist but assume a role at specific stages of MDD [235].”
Background
Impaired regulatory T cell control of astroglial overdrive and microglial pruning in schizophrenia
Zuelli, F. M. D. G. C., & Deakin, J. F. W. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.03.004 · Cited by 90
The cytokine network in the pathogenesis of major depressive disorder. Close to translation?
Petralia, M. C., Mazzon, E., Fagone, P., Basile, M. S., Lenzo, V., Quattropani, M. C. A., Nuovo, S. D., Bendtzen, K., & Nicoletti, F. (2020) · Autoimmunity Reviews · doi:10.1016/j.autrev.2020.102504 · Cited by 89
Evidence for the Role of Mitochondrial DNA Release in the Inflammatory Response in Neurological Disorders
Moya, G. E., Rivera, P. D., & Dittenhafer‐Reed, K. E. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22137030 · Cited by 90
Is there neuroinflammation in depression? Understanding the link between the brain and the peripheral immune system in depression
Nettis, M. A., & Pariante, C. M. (2020) · International review of neurobiology · doi:10.1016/bs.irn.2019.12.004 · Cited by 83
Self-citation
Increased GFAP concentrations in the cerebrospinal fluid of patients with unipolar depression
Michel, M., Fiebich, B. L., Kuzior, H., Meixensberger, S., Berger, B., Maier, S., Nickel, K., Runge, K., Denzel, D., Pankratz, B., et al. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01423-6 · Cited by 79
Is depression the missing link between inflammatory mediators and cancer?
Polityńska, B., Pokorska, O., Wojtukiewicz, A. M., Sawicka, M., Mysliwiec, M., Honn, K. V., Tucker, S. C., & Wojtukiewicz, M. Z. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2022.108293 · Cited by 83
Major depressive disorder as a neuro-immune disorder: Origin, mechanisms, and therapeutic opportunities
Réus, G. Z., Manosso, L. M., Quevedo, J., & Carvalho, A. F. (2023) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2023.105425 · Cited by 94
A systematic review of the association between biological markers and environmental stress risk factors for adolescent depression
Zajkowska, Z., Walsh, A. E. L., Zonca, V., Gullett, N., Pedersen, G. A., Kieling, C., Swartz, J. R., Karmacharya, R., Fisher, H. L., Kohrt, B. A., et al. (2021) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2021.04.003 · Cited by 87
Self-citation
Translational evidence for the Inflammatory Response System (IRS)/Compensatory Immune Response System (CIRS) and neuroprogression theory of major depression
Debnath, M., Berk, M., & Maes, M. H. J. (2021) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2021.110343 · Cited by 77
Beyond the neuron: Role of non-neuronal cells in stress disorders
Cathomas, F., Holt, L. M., Parise, E. M., Liu, J., Murrough, J. W., Casaccia, P., Nestler, E. J., & Russo, S. J. (2022) · Neuron · doi:10.1016/j.neuron.2022.01.033 · Cited by 72
TSPO PET brain inflammation imaging: A transdiagnostic systematic review and meta-analysis of 156 case-control studies
Picker, L. D., Morrens, M., Branchi, I., Haarman, B. C. M., Terada, T., Kang, M. S., Boche, D., Tremblay, M., Leroy, C., Bottlaender, M., et al. (2023) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2023.07.023 · Cited by 87
Microglial Inflammatory-Metabolic Pathways and Their Potential Therapeutic Implication in Major Depressive Disorder
Rahimian, R., Belliveau, C., Chen, R., & Mechawar, N. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.871997 · Cited by 77
Anti-inflammatory properties of commonly used psychiatric drugs
Patel, S., Keating, B. A., & Dale, R. C. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.1039379 · Cited by 70
How Oxidative Stress Induces Depression?
Ji, N., Lei, M., Chen, Y., Tian, S., Li, C., & Zhang, B. (2023) · ASN NEURO · doi:10.1177/17590914231181037 · Cited by 84
“…IL-6 and TNF-α in the serum Lindqvist et al. (2017); Zou et al. (2018) Increased IL-6, TNF-α and TSPO in multiple brain subregions (ACC/PFC/hippocampus) Enache et al. (2019); Gritti et al. (2021) Behavioral therapy reduces peripheral IL-6 Ma et al. (2022) Fluoxetine reduces IL-1β, IL-6 and TNF-α…”
Background
Neuroinflammation in Major Depressive Disorder: A Review of PET Imaging Studies Examining the 18-kDa Translocator Protein
Gritti, D., Delvecchio, G., Ferro, A., Bressi, C., & Brambilla, P. (2021) · Journal of Affective Disorders · doi:10.1016/j.jad.2021.06.001 · Cited by 69
Stress-Related Dysfunction of Adult Hippocampal Neurogenesis—An Attempt for Understanding Resilience?
Leschik, J., Lutz, B., & Gentile, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147339 · Cited by 77
Distinct non-inflammatory signature of microglia in post-mortem brain tissue of patients with major depressive disorder
Snijders, G. J. L., Sneeboer, M. A. M., Fernández-Andreu, A., Udine, E., (NBB-Psy), P. D. P. O. T. N. B. B., Boks, M. P., Ormel, P. R., van Berlekom, A. B., van Mierlo, H. C., Böttcher, C., et al. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-00896-z · Cited by 66
Cannabidiol antidepressant-like effect in the lipopolysaccharide model in mice: Modulation of inflammatory pathways
Florensa-Zanuy, E., Garro-Martínez, E., Adell, A., Castro, E., Díaz, Á., Pazos, Á., MacDowell, K. S., Martín‐Hernández, D., & Pilar-Cuéllar, F. (2021) · Biochemical Pharmacology · doi:10.1016/j.bcp.2021.114433 · Cited by 68
How environmental enrichment balances out neuroinflammation in chronic pain and comorbid depression and anxiety disorders
Kimura, L. F., Novaes, L. S., Picolo, G., Munhoz, C. D., Cheung, C. W., & Camarini, R. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15584 · Cited by 74
Novel rapid-acting glutamatergic modulators: Targeting the synaptic plasticity in depression
Wang, Y., Wang, X., Feng, S., Chen, N., Wang, Z., & Zhang, Y. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105761 · Cited by 68
Microglia and their LAG3 checkpoint underlie the antidepressant and neurogenesis-enhancing effects of electroconvulsive stimulation
Rimmerman, N., Verdiger, H., Goldenberg, H., Naggan, L., Robinson, E., Kozela, E., Gelb, S., Reshef, R., Ryan, K. M., Ayoun, L., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01338-0 · Cited by 62
Brain-immune crosstalk in the treatment of major depressive disorder
Branchi, I., Poggini, S., Capuron, L., Benedetti, F., Poletti, S., Tamouza, R., Drexhage, H. A., Penninx, B. W. J. H., & Pariante, C. M. (2020) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2020.11.016 · Cited by 66
Self-citation
The association of child maltreatment and systemic inflammation in adulthood: A systematic review
Kerr, D. M., McDonald, J. J., & Minnis, H. (2021) · PLoS ONE · doi:10.1371/journal.pone.0243685 · Cited by 71
Adverse childhood experiences and depressive symptoms in later life: Longitudinal mediation effects of inflammation
Iob, E., Lacey, R. E., & Steptoe, A. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.07.045 · Cited by 70
“Meta-analyses of the literature have indicated that depressed individuals tend to have elevated concentrations of various inflammatory markers, both peripherally and in the brain (Haapakoski et al., 2015; Enache et al., 2019).”
Background
Longitudinal relationships of cytokines, depression and anhedonia in depressed adolescents
Rengasamy, M. L., Marsland, A. L., McClain, L. L., Kovats, T., Walko, T. D., Pan, L. A., & Price, R. B. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.09.004 · Cited by 65
“Several meta-analyses in adults have robustly demonstrated cross-sectional elevations of proinflammatory cytokines in depressed individuals as compared to healthy controls, most consistently the cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα) (Osimo et al., 2020; Dowlati et al., 2010; Enache et a…”
Background
Advancing an Inflammatory Subtype of Major Depression
Miller, A. H. (2025) · American Journal of Psychiatry · doi:10.1176/appi.ajp.20250289 · Cited by 93
“Evidence of increased inflammation is also found in postmortem brain samples of patients with depression, including increased levels of inflammatory signaling molecules in brain parenchyma (8) and the presence of macrophages and activated microglia (9) (the immune cells of the brain), as well as increased levels of in…”
Paeoniflorin exerts antidepressant-like effects through enhancing neuronal FGF-2 by microglial inactivation
Cheng, J., Chen, M., Wan, H., Chen, X., Li, C., Zhu, J., Liu, Q., Xu, G., & Yi, L. (2021) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2021.114046 · Cited by 66
Potential Role of Curcumin for the Treatment of Major Depressive Disorder
Lopresti, A. L. (2022) · CNS Drugs · doi:10.1007/s40263-022-00901-9 · Cited by 72
Remodeling of microbiota gut-brain axis using psychobiotics in depression
Palepu, M. S. K., & Dandekar, M. P. (2022) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2022.175171 · Cited by 62
Inflammation, stress and depression: An exploration of ketamine’s therapeutic profile
Johnston, J. N., Greenwald, M. S., Henter, I. D., Kraus, C., Mkrtchian, A., Clark, N. G., Park, L. T., Gold, P. W., Zarate, C. A., & Kadriu, B. (2023) · Drug Discovery Today · doi:10.1016/j.drudis.2023.103518 · Cited by 68
Neuroinflammation as measured by positron emission tomography in patients with recent onset and established schizophrenia: implications for immune pathogenesis
Conen, S., Gregory, C. J., Hinz, R., Smallman, R. P., Zuelli, F. M. D. G. C., Deakin, J. F. W., & Talbot, P. S. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-0829-y · Cited by 67
Inflammation-Related Changes in Mood Disorders and the Immunomodulatory Role of Lithium
Sakrajda, K., & Szczepankiewicz, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22041532 · Cited by 65
“Recent studies have described the effect of an elevated expression of TSPO and VDAC on both gene and protein levels in the group of BD and MDD patients, as compared to controls [40,75,76].”
Result
Sickness behaviour and depression: An updated model of peripheral-central immunity interactions
Turkheimer, F., Veronese, M., Mondelli, V., Cash, D., & Pariante, C. M. (2023) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2023.03.031 · Cited by 69
“, 2009) but results in MDD were mixed with 2/3 of the studies reporting reductions or no-change of IL-6 and TNF- concentrations and the remaining registering moderate increases (Enache et al., 2019).”
ResultSelf-citation
Pro-inflammatory cytokines in stress-induced depression: Novel insights into mechanisms and promising therapeutic strategies
Chang, J., Jiang, T., Shan, X., Zhang, M., Li, Y. Y., Qi, X., Bian, Y., & Zhao, L. (2024) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2023.110931 · Cited by 72
No evidence for clinical efficacy of adjunctive celecoxib with vortioxetine in the treatment of depression: A 6-week double-blind placebo controlled randomized trial
Baune, B. T., Sampson, E., Louise, J., Hori, H., Schubert, K. O., Clark, S. R., Mills, N. T., & Fourrier, C. (2021) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2021.07.092 · Cited by 62
Esketamine Prevents Postoperative Emotional and Cognitive Dysfunction by Suppressing Microglial M1 Polarization and Regulating the BDNF-TrkB Pathway in Ageing Rats with Preoperative Sleep Disturbance
Wen, Y., Xu, J., Shen, J., Tang, Z., Li, S., Zhang, Q., Li, J., & Sun, J. (2024) · Molecular Neurobiology · doi:10.1007/s12035-023-03860-4 · Cited by 71
“…stimuli and adopt a proinflammatory state that produces proinflammatory cytokines, such as tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6(IL-6), nitric oxide (NO), and reactive oxygen species (ROS), which are consistently upregulated in depression patients [8, 9].”
Background
Behavioral comorbidities of epilepsy and neuroinflammation: Evidence from experimental and clinical studies
Suleymanova, E. M. (2021) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2021.107869 · Cited by 62

Authors: Enache, D., Pariante, C. M., & Mondelli, V.
Affiliations: King's College London (GB)
National Health Service (GB)
Corresponding author: Mondelli, Valeria
ORCID: Enache, Daniela
Pariante, Carmine M.
Mondelli, Valeria
Venue: Brain, Behavior, and Immunity
Publisher: Elsevier BV
Published: 2019-10
Volume: 81
Pages: 24-40
ISSN: 0889-1591 (ISSN-L)
DOI: 10.1016/j.bbi.2019.06.015
OpenAlex: W2953025937
Semantic Scholar: 83e5363ffd00c2dba7a412e43a5a292f085d67ed
Cited by: 615
References: 97
Citations by year: 2026: 54 · 2025: 74 · 2024: 160 · 2023: 91 · 2022: 86 · 2021: 87 · 2020: 52 · 2019: 11
FWCI: 3.71
Type: journal article
Language: en
Open access: green
kclpure.kcl.ac.uk
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Brain Behavior and Immunity (publishedVersion)
PubMed (publishedVersion)
Research Portal (King's College London) (submittedVersion, cc-by-nc-nd)
Funders: GlaxoSmithKline foundation
South London and Maudsley NHS Foundation Trust
Kingâs College London
Svenska LÃ¤karesÃ¤llskapet (MQBF1)
National Institute for Health Research
Medical Research Foundation (MRF-160-0005)
H. Lundbeck A/S
Wellcome Trust
Medical Research Council
Topics: Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
Keywords: major depressive disorder, neuroinflammation, cerebrospinal fluid cytokines, interleukin-6, TNF-α, translocator protein (TSPO), positron emission tomography, microglia, astrocytes, oligodendrocytes, suicide attempters, postmortem brain, peripheral inflammation, prefrontal cortex, anterior cingulate cortex
MeSH terms: Astrocytes, Autopsy, Brain, Major Depressive Disorder, Female, Humans, Inflammation, Male, Oligodendroglia, Tumor Necrosis Factor-alpha, Biomarkers, Interleukin-6, Cytokines, Prefrontal Cortex, Microglia, Receptors, GABA, Chemokines, Positron-Emission Tomography

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

A second model labelled each claim on 2026-10-07 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Markers of central inflammation in major depressive disorder: A systematic review and meta-analysis of studies examining cerebrospinal fluid, positron emission tomography and post-mortem brain tissue

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Self-check

Citations

Cites

Cited by

Related

Metadata

Record

About these checks